Uncovering the mechanism for aggregation in repeat expanded RNA reveals a reentrant transition

RNA molecules aggregate under certain conditions. The resulting condensates are implicated in human neurological disorders, and can potentially be designed towards specified bulk properties in vitro. However, the mechanism for aggregation—including how aggregation properties change with sequence and environmental conditions—remains poorly understood. To address this challenge, we introduce an analytical framework based on multimer enumeration. Our approach reveals the driving force for aggregation to be the increased configurational entropy associated with the multiplicity of ways to form bonds in the aggregate. Our model uncovers rich phase behavior, including a sequence-dependent reentrant phase transition, and repeat parity-dependent aggregation. We validate our results by comparison to a complete computational enumeration of the landscape, and to previously published molecular dynamics simulations. Our work unifies and extends published results, both explaining the behavior of CAG-repeat RNA aggregates implicated in Huntington’s disease, and enabling the rational design of programmable RNA condensates.